A mutation in Rab27a causes the vesicle transport defects observed in ashen mice
A mutation in Rab27a causes the vesicle transport defects observed in ashen mice
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DOI：
10.1073/pnas.140212797
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发表时间：
2000-07-05
影响因子：
11.1
通讯作者：
Jenkins, NA
中科院分区：
文献类型：
--
作者：
Wilson, SM;Yip, R;Jenkins, NA
稀释（d），铅（ln），和灰色（灰）突变提供了一个独特的模型系统，研究囊泡运输哺乳动物。这三种突变都是由于色素颗粒运输的缺陷而导致毛色变浅。此外，所有三种突变都受到半显性稀释抑制因子（dsu）的抑制，这提供了遗传学证据表明这些突变在相同或重叠的转运途径中发挥作用。先前的研究表明，d编码一种主要的囊泡转运马达，肌球蛋白-VA，其在Griscelli综合征患者中发生突变。在这里，使用定位克隆和细菌人工染色体拯救，我们表明，灰编码Rab 27 a，Rab GTP酶代表的p21 Ras超家族的最大分支，并被认为是在真核细胞中的囊泡运输和细胞器动力学的关键球员。我们还表明，灰鼠有血小板缺陷，导致出血时间增加和血小板致密颗粒数量减少。这些缺陷尚未报告的d和In小鼠。总的来说，我们的研究确定Rab 27 a作为黑素细胞和血小板中细胞器特异性蛋白运输的关键基因，并表明Rab 27 a在MyoVa依赖和独立途径中发挥作用。
The dilute (d), leaden (ln), and ashen (ash) mutations provide a unique model system for studying vesicle transport in mammals. All three mutations produce a lightened coat color because of defects in pigment granule transport. In addition, all three mutations are suppressed by the semidominant dilute-suppressor (dsu), providing genetic evidence that these mutations function in the same or overlapping transport pathways, Previous studies showed that d encodes a major vesicle transport motor, myosin-VA, which is mutated in Griscelli syndrome patients. Here, using positional cloning and bacterial artificial chromosome rescue, we show that ash encodes Rab27a, Rab GTPases represent the largest branch of the p21 Ras superfamily and are recognized as key players in vesicular transport and organelle dynamics in eukaryotic cells. We also show that ash mice have platelet defects resulting in increased bleeding times and a reduction in the number of platelet dense granules. These defects have not been reported for d and In mice. Collectively, our studies identify Rab27a as a critical gene for organelle-specific protein trafficking in melanocytes and platelets and suggest that Rab27a functions in both MyoVa dependent and independent pathways.